Voltage-dependent Ca2+ channels have evolved to regulate physiological processes as diverse as gene transcription and muscle contraction. In the central nervous system, several structurally and pharmacologically distinct Ca2+ channel types are co-localized in nerve terminals, and, jointly, they control exocytosis. As the minor biophysical differences among these exocytotic Ca2+ channels are unlikely to provide much variation in excitation-secretion coupling, the biological rationale underlying their co-localization in nerve terminals is unclear. Experiments in this application will explore the hypothesis that each of these channel types is uniquely regulated by biochemical pathways activated by extracellular transmitters. Such differential modulation of the channels might, in part, underlie activity-dependent changes in synaptic strength, such as long-term depression or potentiation. Proposed investigations will focus on two specific Ca2+ channel types--N and P-- each to be separately studied in embryonic chick sensory neurons. Experiments will I) describe the modulatory pathways that control N channels, 2) determine whether P channels are similarly modulated, 3) study activity-dependent variation in modulatory efficacy, and 4) assess the physiological significance of differential modulation at the level of transmitter release. Results will help to sort out the complex network of biochemical pathways that impinge on voltage-dependent Ca2+ channels and offer insight into the organizing principles fundamental to synaptic plasticity and, ultimately, to cognitive processing in the nervous system.